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Mitochondrial Physiology

Calcium homeostasis and oxidative stress

Due to their large negative membrane potential, mitochondria can accumulate significant amounts of Ca2+ provided that the ambient Ca2+ concentration is sufficiently high. The latter is achieved by close juxtaposition of these organelles against the endoplasmic reticulum (ER), which forms the major source of Ca2+ ions during cellular stimulation. The increase in mitochondrial Ca2+ concentration causes a boost in mitochondrial ATP production, thus allowing the rapid balancing of local energy demand.

Using a combination of luminometry (cell groups) and digital imaging microscopy (single cells), we have found that Ca2+-stimulated mitochondrial ATP production is decreased in skin fibroblasts of patients with inherited complex I deficiency and that this decrease is mainly due to a pathological reduction in ER Ca2+ content. Thus far, we have shown that drugs that normalize the agonist-induced increase in mitochondrial Ca2+ concentration also normalize the agonist-induced increase in mitochondrial ATP production.

Our findings are of eminent importance because they provide possible drug targets for the amelioration of the condition of patients suffering from isolated complex I deficiency. New projects will be started to evaluate possible beneficial effects of drugs that interfere with Ca2+-stimulated mitochondrial ATP production.